The SardiNIA study population cohort comprises over 7,000 subjects, starting at ages from 14-102, from a cluster of four towns in Sardinia. The study has been measuring >300 quantitative traits (endophenotypes or quantitative risk-related genetic or environmental factors) that can be scored on a continuous scale. Traits of special interest include a range of cardiovascular risk factors, anthropometric measurements, blood test values, and facets of personality. Fourth visits are now in progress for the study cohort to permit the assessment of longitudinal trends and outcomes, as well as the assessment of additional phenotypes related to bone density and frailty as a function of age. For example, 24 hour blood pressure measurements and ECHOcardiography is extending the analysis of cardiovascular traits;and the cohort is being specifically extended to over 250 individuals over 92 years of age to analyze effects of extreme age. With this cohort, full-genome scans with batteries of single-nucleotide markers were conducted, and were supplemented in the last year with full genome DNA sequencing and genotyping with specialized chips (metabochip, immunochip, and exome chip, and a chip designed to give equal coverage across the entire genome). These have provided a catalogue of over 17,000,000 variants, including a range of relatively rare variants, which are being tested for association with traits and diseases in Genome-wide association scans (GWAS). In a further extension of genomic analyses, ribosomal DNA and centromeric sequences will be sequenced in the coming year;these will provide additional variants for genetic analyses. In addition, 1,000 individuals have provided lymphocyte RNA samples for sequence analysis, permitting more incisive estimates of variants of levels of different genomic RNA transcripts and changes of expression influenced by individual DNA. In studies thus far, GWAS have pointed to genes/variants that determine a significant portion of the genetic contribution to variance for each trait and disease studied. In conjunction with consortium efforts on other population cohorts, including the Baltimore Longitudinal Study of Aging and the InCHIANTI study supported by the NIA, an increasing number of publications have resulted that identify genes associated with obesity, cardiovascular traits, and levels of lipids and blood components. In particular, genes associated with HbF levels as a modulator of thalassemia/sickle cell disease severity have been identified, as well as findings of genetic factors determining loci for blood pressure, many affecting adiposity;and personality facets affecting under- and over-weight (see bibliography for a complete list). In an additional new initiative in the past year, the levels of 91 immune system cells were determined for 3,500 participants, and over 200 genetic factors affecting various cells, some of them also associated with risk of autoimmune disease, were identified. In a complementary approach, genetic studies are extended to clinical series of Sardinian patients and controls focusing on autoimmune diseases, all of which have a very high incidence on the island. In an initial report on multiple sclerosis, a gene was identified (CBLB) that regulates the level of the immune response both in patients in Sardinia and in other populations and in a mouse model for the disease;and a further report in preparation identifies several additional genes/variants. The combination of the studies of immune system cell levels and autoimmune diseases indicate not only association of variants with disease risk but specification of the cell type(s) in which those variants have their affects. This provides a further step in supplying markers and potential molecular and cellular targets for possible eventual intervention.